Journal Article

DZNE-2021-01512

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures.

Kreye, J. (First author)DZNE* ; Wright, S. K. ; Casteren, A.DZNE* ; Stöffler, L. ; Machule, M.-L.DZNE* ; Reincke, M.DZNE* ; Nikolaus, M. ; Hoof, S.DZNE* ; Sanchez Sendin, E.DZNE* ; Homeyer, M. A.DZNE* ; Cordero Gomez, C.DZNE* ; Kornau, H.-C.DZNE* ; Schmitz, D.DZNE* ; Kaindl, A. M. ; Boehm-Sturm, P. ; Mueller, S. ; Wilson, M. A. ; Upadhya, M. A. ; Dhangar, D. R. ; Greenhill, S. ; Woodhall, G. ; Turko, P. ; Vida, I. ; Garner, C. C.DZNE* ; Wickel, J. ; Geis, C. ; Fukata, Y. ; Fukata, M. ; Prüß, H. (Last author)DZNE*

2021
Rockefeller Univ. Press New York, NY

This record in other databases:    

Please use a persistent id in citations: doi:10.1084/jem.20210012

Abstract: Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients' symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies.

Keyword(s): Animals (MeSH) ; Antibodies, Monoclonal: immunology (MeSH) ; Autoantibodies: immunology (MeSH) ; Autoantigens: immunology (MeSH) ; Cells, Cultured (MeSH) ; Encephalitis: immunology (MeSH) ; Epilepsy: immunology (MeSH) ; HEK293 Cells (MeSH) ; Hippocampus: immunology (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Neurons: immunology (MeSH) ; Receptors, GABA-A: immunology (MeSH) ; Seizures: immunology (MeSH)

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Contributing Institute(s):

1. Autoimmune Encephalopathies (AG Prüß)
2. Synaptopathy (AG Garner)
3. Network Dysfunction (AG Schmitz)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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